Transdermal therapeutic system containing tulobuterol hydrochloride for administering the bronchodilator tulobuterol via the skin

ABSTRACT

A transdermal therapeutic system comprising a largely water vapor-impermeable backing layer, at least one active substance-containing matrix layer comprising the active substance tulobuterol, as well as a removable protective layer, is characterized in that said matrix is built-up on the basis of polyacrylate pressure-sensitive adhesives and contains tulobuterol in the form of its salt tulobuterol hydrochloride as active substance.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/EP00/09788 which has an Internationalfiling date of Oct. 6, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a transdermal therapeutic system containingtulobuterol hydrochloride, which system enables the administration ofthe bronchodilator tulobuterol via the skin. The transdermal medicinalpreparation is suitable for treatment of asthmatic diseases.

2. Description of the Related Art

Tulobuterol is a medicinal agent from the group of theβ-sympathomimetics. It is predominantly active on the β₂-receptors ofnon-striated muscles, for example, in the bronchi. Due to its having theproperties of reducing the bronchial muscular tone and effecting arelaxation of the bronchial muscles, tulobuterol is being used in thetherapy of asthmatic diseases.

Apart from oral administration forms, from the literature there are alsoknown transdermal application systems for tulobuterol which can besuccessfully utilized in asthma therapy. Transdermal therapeutic systemscontaining tulobuterol have been described, for example, in JP 63-10716A, U.S. Pat. No. 5,254,348, U.S. Pat. No. 5,312,627, U.S. Pat. No.5,571,536 and U.S. Pat. No. 5,639,472.

U.S. Pat. No. 5,254,348 discloses a transdermal therapeutic system thetulobuterol-containing matrix of which is built-up on the basis of astyrene-1,3-diene-styrene block copolymer or a styrene-isoprene-styreneblock copolymer.

U.S. Pat. No. 5,312,627 describes a transdermal therapeutic systemsuitable for administering active substances having bronchodilatoryaction, e.g. tulobuterol. As a matrix polymer, polyisobutylene is used.

In U.S. Pat. No. 5,571,530 there is likewise described a percutaneouscomposition comprising the active substance tulobuterol, with the activesubstance being present in a polymer matrix made up of a mixture ofpolyisobutylenes.

From U.S. Pat. No. 5,639,472 there is known a tulobuterol-containingcomposition suitable for percutaneous absorption. It is characterized bythe fact that tuloburetol is present both in dissolved as well as incrystalline form in the pressure-sensitive adhesive layer of theplaster.

Finally, in EP 0 922 453 A2 there is disclosed a device for thepercutaneous administration of tulobuterol. This administration formcomprises a pressure-sensitive adhesive acrylate layer containing atleast 5%-wt. of tulobuterol as free active substance base in completelydissolved condition. The active substance remains dissolved so thatthere is no loss of action by crystallization.

A suggestion as to the possible use of salts of tulobuterol or even ofthe hydrochloride is not found in EP 0 922 453 A2.

In the above-described tulobuterol-containing transdermal therapeuticsystems, tulobuterol is preferably utilized as a free base, the reasonfor this being that the free base on account of its hydrophobiccharacter can be readily absorbed via the skin, whereas the salts oftulobuterol (e.g. tulobuterol hydrochloride) are more stronglyhydrophile, which results in a poorer ability to penetrate the skin. Forthis reason tulobuterol hydrochloride has heretofore only been used forperoral therapy, but not for transdermal administration. Only U.S. Pat.No. 5,254,348 also mentions, in general terms, the pharmaceuticallyacceptable salts of tulobuterol, without, however, dealing in moredetail with the problem of the hydrophilicity or of the poorer capacityfor skin penetration of the salts.

Apart from its poorer capacity to penetrate the skin, the use oftulobuterol hydrochloride instead of the free base also affords someremarkable advantages. Firstly, it has been used in asthma therapy for amuch longer time and on a far wider scale. This means that one is ableto have recourse to considerably more extensive material relating to thetoxicology and pharmacology of this active substance. Secondly, due toits being used world-wide on a larger scale, tulobuterol hydrochlorideis obtainable on commercially more favourable conditions and from agreater number of sources of supply than the free base. It is alsoconsidered an advantage that tulobuterol hydrochloride ismonographically described in the Japanese pharmacopoeia (JP XIII).Therefore—by contrast to the case of tulobuterol—there already exists apharmaceutical quality standard which can be made use of for world-wideapproval.

SUMMARY OF THE INVENTION

It was therefore the object of the present invention to provide atransdermal administration form which enables the administration oftulobuterol in the form of its salt tulobuterol hydrochloride, and whichhas the advantages entailed in the use of tulobuterol hydrochloride.

In addition, with such transdermal administration form the intention isto obtain skin permeation rates sufficient to ensure therapeuticapplication.

This object is surprisingly achieved by a transdermal therapeutic systemaccording to the invention that has a structure comprising a largelywater vapour-impermeable backing layer, at least one activesubstance-containing matrix layer and a removable protective layer. Thepharmaceutical product according to the present invention containstulobuterol in the form of its salt tulobuterol hydrochloride, theactive substance being present in a polymer matrix that is built-up onthe basis of polyacrylate pressure-sensitive adhesives.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of the skin permeation of tolubuterol hydrochloridevs. time. The measurements were made using Examples 1 to 4 of Table 1.

DETAILED DESCRIPTION

Using tulobuterol hydrochloride, permeation rates of tulobuterol throughhuman skin in vitro of more than 300 μg/cm²·d were achieved by means ofthe application system according to the invention (cf. FIG. 1). In viewof the fact that this substance is a relatively hydrophile salt form ofan active agent, this is a surprisingly high permeation rate. It isassumed that tulobuterol hydrochloride, after its release from the TTS,permeates through the skin in the form of the free base tulobuterol.

By means of the administration form of the invention the daily doses of0.5 to 6 mg of tulobuterol hydrochloride, which are usual in peroraladministration, can be administered also via the transdermal route.Preferably, the transdermally administrable daily doses are in the rangeof 2 to 4 mg. The duration of application may extend up to three daysand beyond. Thus, because of their active substance releasecharacteristics the tulobuterol hydrochloride-containing transdermaltherapeutic systems described herein are suitable for therapeutic use,for example, in cases of asthmatic diseases.

The active substance content of the matrix or the active substanceconcentration can be varied in wide ranges. In a preferred embodiment ofthe invention the mass content of tulobuterol hydrochloride lies in arange of 2.5 to 20%, preferably in a range of 5 to 10%, relative to thetotal mass of the active substance-containing matrix.

The base substance of the matrix layer or matrix layers, of which atleast one has a content of tulobuterol hydrochloride, is built-up on thebasis of polyacrylate pressure-sensitive adhesives. Polymers or polymermixtures suitable for this purpose are known to those skilled in theart; to be considered are first of all polyacrylic, polymethacrylic, andpolymethylmethacrylic acid and their derivatives as well as acrylic-acidester copolymers. To adapt the mechanical properties of the matrix (e.g.cohesion, elasticity) to specific requirements, it is possible to addfurther polymers, for example, polyvinyl acetate, silicone polymers,polyisobutylenes, polyisoprene or styrene-containing block copolymers.

Particularly good results can be obtained with an embodiment of theinvention wherein the polymer composition of the activesubstance-containing matrix contains a polymer having amino-functionalgroups in its side chains. The mass portion of this polymer amounts to 2to 20%, preferably 10 to 16%, relative to the mass of the activesubstance-containing matrix. Preferably, as the polymer withamino-functional groups, a butylmethacrylate-(2-dimethyl-aminoethyl)-methyl methacrylate copolymerwherein the monomers are present in the molar ratio of 1:2:1 (=Eudragit®E-100) is used.

In the simplest case, the transdermal system according to the presentinvention comprises—besides the backing and the protective layer—only asingle active substance-containing matrix layer. An especially preferredembodiment is, however, one characterized by a second matrix layer,likewise containing tulobuterol hydrochloride. The two activeagent-containing layers are in this case laminated upon each other. Theextent of the active substance load may be selected so as to be the samein both layers, but may also be chosen to be different. Typically, thetwo active substance-containing layers will have the same content ofadditives. For certain applications it may, however, be of advantage ifthe two layers differ from each other in respect of their content ofadditives. It is also possible to choose different polymer compositionsfor the matrix.

A further preferred embodiment variant provides that in the stateimmediately following manufacture, at least one of the matrix layersdoes not contain active substance. For example, in the case of atwo-layer matrix the skin-facing matrix layer can be free of activeagent, whereas the second matrix layer (reservoir layer) locateddirectly thereabove contains tulobuterol hydrochloride. Aftermanufacture and during the application period the active substancediffuses from the latter layer into the skin-facing, previously activesubstance-free matrix layer, from which the permeation into the skin cantake place. The manufacture of the latter active substance patches isadvantageous in terms of production logistics, one has to acceptslightly lower rates of active substance release, however.

In certain cases it may be advantageous if the therapy with tulobuterolis combined with the therapy with one or more additional activesubstances. For this reason, there are provided further embodimentswherein at least one further matrix layer contains one or more furtherpharmaceutical active agents.

To improve the release of tulobuterol hydrochloride it is, in addition,possible to add skin permeation-enhancing additives to the matrixlayers. Especially suitable for this purpose are saturated orunsaturated fatty acids, singly or in combination, preferably lauricacid, myristic acid or oleic acid. The matrix layer may have a contentof 2 to 20%, preferably 5 to 10%, of fatty acids, relative to the totalmass of the matrix layers. Combinations of different fatty acids may beused to advantage.

Suitable as permeation-enhancing additives are furthermore substancesfrom the group of low-molecular mono- or polyvalent alcohols, fattyalcohols, fatty alcohol ethers, polyoxyethylated fatty alcohols, fattyacid esters (especially monoglycerides and monoesters with propyleneglycol), as well as sorbitan fatty acid esters and polyoxyethylatedsorbitan fatty acid esters.

Furthermore, the active substance-containing matrix layers may containplasticizers, tackifiers, cohesion-promoting additives, stabilizers,fillers and similar additives. The substances suitable for this purposeare known to those skilled in the art.

According to a further preferred embodiment, the activesubstance-containing matrix of the tulobuterol hydrochloride-containingtransdermal active substance patches has a weight per unit area of atleast 120 g/m². Such above-average layer-thicknesses of the matrixensure, in particular, a constant, high release rate over a period ofmore than 24 hours.

The materials which can be used for the substantially water-impermeablebacking layer and for the detachable protective layer are known to thoseskilled in the art. For the backing layer, polymer films, above allpolyester, are suitable which are characterized by particular strengthand resistance to diffusion, but apart from these almost any otherskin-tolerable plastics such as polyvinyl chloride, ethylene-vinylacetate, vinyl acetate, polyethylene, polypropylene, cellulosederivatives, and many more. In particular cases, the backing layer maybe provided with an additional overlay, e.g. by vapour-deposition withmetals or other diffusion-blocking additives such as silicon dioxide,aluminium dioxide or similar substances known to those skilled in theart. To improve its outer appearance, the backing layer may also bevarnished skin-coloured on the outer side, or treated in some other way.

Dependent on the strength and permeability of the selected material, thethickness of the film-like backing layer usually is 8 to 80 μm. Forparticular purposes it may, however, also be adjusted to be thicker orthinner than these values.

The detachable protective layer to be removed prior to application ofthe patch is preferably made up of polyester material (e.g. polyethyleneterephthalate film), but any other skin-tolerable plastics may also beused, such as polyvinyl chloride, ethylene-vinyl acetate, vinyl acetate,polyethylene, polypropylene, or cellulose derivatives. In particularcases, vaporization with metals or other diffusion-blocking additivessuch as silicon dioxide, aluminium oxide and the like may be carriedout. In any case, it is necessary to provide a surface coating withdehesive materials, for instance with silicones or fluorine-containingplastics on the side facing the adhesive matrix, for the compound toremain readily detachable.

Especially after a prolonged storage time, slight yellowing can occur inthe tulobuterol HCL-containing TTSs; furthermore, after several months,slight recrystallization was observed as a sign of a certainoversaturation with tulobuterol-HCL. To avoid such unwanted changes,various additives from the field of antioxidants and metal ioncomplexing agents were tested.

It was found that it is possible to achieve particularly effectivesuppression of the yellowing by a combination of a phenolic antioxidantand a polyvalent acid (or its salts). As antioxidant,butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) is utilized withpreference. As acids, citric acid or ethylenediaminetetraacetic acid(EDTA) or its salts, such as disodium EDTA are preferably used. It wassurprisingly found that by adding the abovementioned antioxidants andcomplexing agents, not only will the discolouring be suppressed but atthe same time there will be no recrystallization.

For this reason it is provided in accordance with the best possibleembodiment of the invention that the tulobuterol-containing TTSs containat least one additive from the group of antioxidants, preferablyphenolic compounds, more preferably butylhydroxytoluene orbutylhydroxyanisole, as well as in addition at least one furtheradditive from the group of metal ion complexing agents, preferablycitric acid or ethylenediaminetetraacetic acid, especially preferredethylenediaminetetraacetic acid-disodium salt (Na₂EDTA).

In the following, the invention will be described by means of examples.These examples do not limit the invention in any way.

EXAMPLES

The examples of transdermal therapeutic systems according to theinvention listed in TAB. 1 all have a structure comprising a backinglayer, a tulobuterol hydrochloride-containing reservoir layer (as thefirst matrix layer) and an optionally active substance-free, skin-facingpressure-sensitive adhesive layer. The skin-facing matrix orpressure-sensitive adhesive layer is covered with a removable protectivefilm.

“Optionally active substance-free” means that the skin-facing layer isnot loaded with tulobuterol hydrochloride during manufacture and istherefore free of active substance in the initial state. Aftermanufacture and during application, diffusion of the active substanceoccurs from the reservoir layer through the active substance-freeskin-facing layer in the direction towards the skin, followed by thepermeation of the active substance through the skin.

To prepare the active substance-containing matrix layers, initiallytulobuterol hydrochloride (tulobuterol-HCl) was dissolved in ethanol.Then the other components, including the matrix polymers, were added tothis solution, in the suitable amount of usual organic solvents.

The organic solvents were then coated onto a siliconized polyethyleneterephthalate film (100 μm thickness) using a hand pull frame for films,and dried for 10 min at 80° C. in the exhaust air oven.

The reservoir layer and skin-facing layer obtained in this manner weremechanically laminated to each other, the protective film of thereservoir layer was removed, and this layer was covered with apolyethylene terephthalate film (15 μm thickness) as permanent backinglayer.

The suitability of the examples of application systems preparedaccording to TAB. 1 for a transdermal therapy with tulobuterol wastested on the model of excised human full-thickness skin. The tests weremade using modified permeation cells according to FRANZ at 32° C. in themanner known to those skilled in the art.

Measurements of the quantities of tulobuterol having passed through theskin samples were performed by means of HPLC. The results are shown inFIG. 1.

The values indicated represent the mean value and standard deviation forrespective n=3 skin samples.

Examples 1 and 2 show a structure wherein the skin-facing layer in theinitial state is active agent-free. After manufacture, diffusion of theactive substance takes place into this layer, too. This structure isadvantageous in terms of production logistics, the release rates throughhuman skin obtained in vitro are, however, comparatively low since thesystem as a whole enables only a lower total load with tulobuterol-HCl.

In Examples 3 and 4, tulobuterol-HCl is contained in both layers inequal concentration. The total load is higher than in Examples 1 and 2.This is also reflected in a markedly increased release performance invitro.

Example 3 is slightly superior to Example 4 in respect of its releaserate. The slightly lower portion of Budragit® E100 compared to Example 4obviously at the same has a positive effect on the release performance.

It should be emphasized that in all four examples a linear releasebehaviour is obtained for the active agent tulobuterol which ismaintained for at least up to 72 h (FIG. 1).

Example 5 shows a formulation corresponding to the best possibleembodiment of the invention. Both the skin-facing layer as well as thereservoir layer contain a combination of a phenolic antioxidant(butylhydroxytoluene, BHT) and ethylenediaminetetraacetic acid (disodiumsalt), which results in a reliable prevention of the yellowing of theTTSs and of the recrystallization of the active substance tulobuterolduring the period of storage.

TABLE 1 Weight Exam- Per Unit ple Area Reservoir Layer Skin-Facing No.[g/m²]** Components % Layer % 1 154.3 Tulobuterol-HCl 11.6Tulobuterol-HCl — Eudragit ® E100 13.7 Eudragit ® E100 10.0 Durotak ®2287* 74.7 Durotak ® 2287* 77.5 Oleic Acid — Oleic Acid 12.5 2 166Tulobuterol-HCl 16.3 Tulobuterol-HCl — Eudragit ® E100 19.3 Eudragit ®E100 10.0 Durotak ® 2287* 64.4 Durotak ® 2287* 72.7 Oleic Acid — OleicAcid 17.3 3 162.1 Tulobuterol-HCI 11.6 Tulobuterol-HCI 11.6 Eudragit ®E100 13.7 Eudragit ® E100 15.1 Durotak ® 2287* 68.5 Durotak ® 2287* 67.1Oleic Acid  6.2 Oleic Acid  6.2 4 171.3 Tulobuterol-HCI 11.6Tulobuterol-HCI 11.6 Eudragit ® E100 15.1 Eudragit ® E100 15.1 Durotak ®2287* 67.1 Durotak ® 2287* 67.1 Oleic Acid  6.2 Oleic Acid  6.2 5 159.0Tulobuterol-HCI 11.6 Tulobuterol-HCI 11.6 Eudragit ® E100 13.7Eudragit ® E100 15.1 Durotak ® 2287* 67.9 Durotak ® 2287* 67.1 OleicAcid  6.2 Oleic Acid  6.2 BHT  0.1 BHT  0.1 Na₂EDTA  0.5 Na₂EDTA  0.5*cross-linked by aluminium ions (0.05 mass percent) **relative to thesum of reservoir layer and skin-facing layer

BHT=butylhydroxytoluene; Na₂HDTA=ethylenediaminetetraacetic acid,disodium salt.

The percentages given in the table refer to mass portions (m/m),relative to the total mass of the respective matrix layer.

1. A transdermal therapeutic system comprising: a largely watervapour-impermeable backing layer, at least one activesubstance-containing matrix layer comprising the active substancetulobuterol, and a removable protective layer, wherein said matrix isbased on polyacrylate pressure-sensitive adhesives and containstulobuterol in the form of its salt tulobuterol hydrochloride as theactive substance, and said matrix contains a polymer havingamino-functional groups in its side chains.
 2. The transdermaltherapeutic system according to claim 1 wherein the mass content oftulobuterol hydrochloride is 2.5 to 20%, relative to the mass of theactive substance-containing matrix.
 3. The transdermal therapeuticsystem according to claim 1, wherein the mass content of said polymer is2 to 20%, relative to the mass of the active substance-containingmatrix.
 4. The transdermal therapeutic system according to claim 1,wherein as the polymer having amino-functional groups a butylmethacrylate-(2-dimethylaminoethyl)-methyl methacrylate copolymer isused.
 5. The transdermal therapeutic system according to claim 1,wherein the system also comprises a second tulobuterolhydrochloride-containing matrix layer.
 6. The transdermal therapeuticsystem according to claim 1, wherein in the state immediately after itsmanufacture the system comprises at least one further matrix layer basedon a polyacrylate pressure-sensitive adhesive, which layer does notcontain active substance.
 7. The transdermal therapeutic systemaccording to claim 1, wherein the system contains permeation-enhancingadditives.
 8. The transdermal therapeutic system according to claim 1,wherein the system contains one or more fatty acids in the matrix layer,said fatty acid(s) being contained in a concentration of 2 to 20%,relative to the total mass of the matrix.
 9. The transdermal therapeuticsystem according to claim 1, wherein the system enables the transdermaladministration of common daily doses from 0.5 up to maximally 6 mg, oftulobuterol hydrochloride over an application period of at least 3 days.10. The transdermal therapeutic system according to claim 1, wherein atleast one matrix layer contains one or more additional pharmaceuticallyactive substances.
 11. The transdermal therapeutic system according toclaim 1, wherein the weight per unit area of the activesubstance-containing matrix is at least 120 g/m².
 12. The transdermaltherapeutic system according to claim 1, wherein the system contains atleast one additive comprising an antioxidant.
 13. The transdermaltherapeutic system according to claim 12, wherein the system contains atleast one further additive comprising a metal ion complexing agent. 14.The transdermal therapeutic system according to claim 1, wherein thematrix contains 67% or greater of polyacrylate pressure- sensitiveadhesives.
 15. A method for the treatment of asthma and related forms ofdisease, which comprises: applying to the skin of a person affected byone of said diseases a transdermal therapeutic system according toclaim
 1. 16. The transdermal therapeutic system according to claim 8,wherein said fatty acid(s) are at least one compound selected from thegroup consisting of lauric acid, myristic acid and oleic acid.
 17. Thetransdermal therapeutic system according to claim 12, wherein saidantioxidant comprises a phenolic compound that is butylhydroxytoluene orbutylhydroxyanisole.
 18. The transdermal therapeutic system according toclaim 13, wherein said metal ion complexing agent comprises citric acid,ethylenediaminetetraacetic acid or ethylenediaminetetraaceticacid-disodium salt (Na₂EDTA).
 19. The transdermal therapeutic systemaccording to claim 1, wherein the mass content of tulobuterolhydrochloride is 5 to 10%, relative to the mass of the activesubstance-containing matrix.
 20. The transdermal therapeutic systemaccording to claim 1, wherein the active substance-containing matrixcontains a polymer having amino-functional groups in its side chains andthat the mass content of said polymer is 10 to 16%, relative to the massof the active substance-containing matrix.
 21. The transdermaltherapeutic system according to claim 1, wherein the system contains oneor more fatty acids in the matrix layer, said fatty acid(s) beingcontained in a concentration of 5 to 10%, relative to the total mass ofthe matrix.
 22. A transdermal therapeutic system comprising: a largelywater vapour-impermeable backing layer, at least one activesubstance-containing matrix layer comprising the active substancetulobuterol, and a removable protective layer, wherein said matrix isbased on polyacrylate pressure-sensitive adhesives and containstulobuterol in the form of its salt tulobuterol hydrochloride as theactive substance, and the system also comprises a second tulobuterolhydrochloride-containing matrix layer.
 23. A transdermal therapeuticsystem comprising: a largely water vapour-impermeable backing layer, atleast one active substance-containing matrix layer comprising the activesubstance tulobuterol, and a removable protective layer, wherein saidmatrix is based on polyacrylate pressure-sensitive adhesives andcontains tulobuterol in the form of its salt tulobuterol hydrochlorideas the active substance, and in the state immediately after itsmanufacture the system comprises at least one further matrix layer basedon a polyacrylate pressure-sensitive adhesive, which layer does notcontain active substance.
 24. A transdermal therapeutic systemcomprising: a largely water vapour-impermeable backing layer, at leastone active substance-containing matrix layer comprising the activesubstance tulobuterol, and a removable protective layer, wherein saidmatrix is based on polyacrylate pressure-sensitive adhesives andcontains tulobuterol in the form of its salt tulobuterol hydrochlorideas the active substance, and the system permits the transdermaladministration of common daily doses from 0.5 up to maximally 6 mg, oftulobuterol hydrochloride over an application period of at least 3 days.25. A transdermal therapeutic system comprising: a largely watervapour-impermeable backing layer, at least one activesubstance-containing matrix layer comprising the active substancetulobuterol, and a removable protective layer, wherein said matrix isbased on polyacrylate pressure-sensitive adhesives and containstulobuterol in the form of its salt tulobuterol hydrochloride as theactive substance, and at least one matrix layer contains one or moreadditional pharmaceutically active substances.
 26. A transdermaltherapeutic system comprising: a largely water vapour-impermeablebacking layer, at least one active substance-containing matrix layercomprising the active substance tulobuterol, and a removable protectivelayer, wherein said matrix is based on polyacrylate pressure-sensitiveadhesives and contains tulobuterol in the form of its salt tulobuterolhydrochloride as the active substance, and the weight per unit area ofthe active substance-containing matrix is at least 120 g/m².